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It is well established that offspring of older men are at increased risk of developing mental illnesses such as schizophrenia and autism spectrum disorder (ASD). Former studies have identified an increasing number of genetic mutations as men age as a contributing factor for this increased risk. In this new NARSAD Grant-supported study, the research team looked for different contributing factors―they studied “epigenetic” effects on genes. Epigenetic effects are factors that alter the expression of genes without altering the underlying DNA or genetic code (whereas genetic mutations actually change the genetic code).

On December 8th, at the annual meeting of the American College of Neuropsychopharmacology in Florida, 2010 NARSAD Young Investigator Grantee, Maria Milekic, Ph.D., reported on behalf of a research team from the Department of Psychiatry at Columbia University that they had identified epigenetic changes that also appeared to be associated with this increased risk. Using animal models, they found that older male mice show a loss of DNA methylation (an epigenetic effect) that gets passed on to offspring and affects their behavior―the mice were less exploratory and had different startle responses than the offspring from younger fathers (without the deficit in DNA methylation). DNA methylation is known to be instrumental in regulating the expression of genes.

"We were interested in understanding the mechanism of the paternal age effect," said Dr. Milekic. “The risk for schizophrenia increases two-fold when a father is over 45 years of age, and the risk for autism increases two- to five-fold. It seemed unlikely that mutation alone could account for this. We therefore speculated that DNA methylation could provide an alternative mechanism."

The research team also found that the offspring of the older fathers had significant differences in the expression of genes that have been implicated in ASD and that are known to regulate the development and function of the brain. These findings point to possible factors that can lead to ASD and schizophrenia, and ultimately may lead to more effective therapeutic interventions.

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